Substituted thieno[2,3-b]thiophene-2-sulfonamides as antiglaucoma agents

ABSTRACT

Aromatic sulfonamides useful in the treatment of elevated intraocular pressure having the structural formula: ##STR1## wherein A, R, R 1 , and R 2  are as hereinafter defined, as well as the pharmaceutically and ophthalmologically acceptable salts thereof.

SUMMARY OF THE INVENTION

This is a continuation-in-part of copending application Ser. No. 191,085filed May 4, 1988, which in turn is a continuation-in-part of copendingapplication Ser. No. 162532 filed Mar. 1, 1988, now abandoned, which inturn is a continuation-in-part of copending application Ser. No. 080851,filed Aug. 3, 1987, now abandoned.

This invention relates to novel aromatic sulfonamides useful in thetreatment of elevated intraocular pressure. More particularly thisinvention relates to compounds having the structural formula: ##STR2##wherein A, R, R¹, and R² are as hereinafter defined, as well as thepharmaceutically and opthalmologically acceptable salts thereof. Thisinvention also relates to pharmaceutical compositions and the usethereof for systemic and ophthalmic use employing a novel compound ofthis invention as active ingredient for the treatment of elevatedintraocular pressure, especially when accompanied by pathological damagesuch as in the disease known as glaucoma. The invention also relates toprocesses for preparation of the novel compounds.

BACKGROUND OF THE INVENTION

Glaucoma is an ocular disorder associated with elevated intraocularpressures which are too high for normal function and may result inirreversible loss of visual function. If untreated, glaucoma mayeventually lead to blindness. Ocular hypertension, i.e., the conditionof elevated intraocular pressure without optic nerve head damage orcharacteristic glaucomatous visual field defects, is now believed bymany ophthalmologists to represent the earliest phase of glaucoma.

Many of the drugs formerly used to treat glaucoma proved not entirelysatisfactory. Indeed, few advances were made in the treatment ofglaucoma since pilocarpine and physostigmine were introduced. Onlyrecently have clinicians noted that many β-adrenergic blocking agentsare effective in reducing intraocular pressure. While many of theseagents are effective in reducing intraocular pressure, they also haveother characteristics, e.g. membrane stabilizing activity, that are notacceptable for chronic ocular use.(S)-1-tert-Butylamino-3-[(4-morpholino-1,2-5-thiadiazol-3-yl)oxyl]-2-propanol,a β-adrenergic blocking agent, was found to reduce intraocular pressureand to be devoid of many unwanted side effects associated withpilocarpine and, in addition, to possess advantages over many otherβ-adrenergic blocking agents, e.g. to be devoid of local anestheticproperties, to have a long duration of activity, and to display minimaltolerance.

Although pilocarpine, physostigmine and the β-blocking agents mentionedabove reduce intraocular pressure, none of these drugs manifests itsaction by inhibiting the enzyme carbonic anhydrase and, thereby,impeding the contribution to aqueous humor formation made by thecarbonic anhydrase pathway.

Agents referred to as carbonic anhydrase inhibitors, block or impedethis inflow pathway by inhibiting the enzyme, carbonic anhydrase. Whilesuch carbonic anhydrase inhibitors are now used to treat intraocularpressure by oral, intravenous or other systemic routes, they therebyhave the distinct disadvantage of inhibiting carbonic anhydrasethroughout the entire body. Such a gross disruption of a basic enzymesystem is justified only during an acute attack of alarmingly elevatedintraocular pressure, or when no other agent is effective. Despite thedesirability of directing the carbonic anhydrase inhibitor only to thedesired ophthalmic target tissue, no topically effective carbonicanhydrase inhibitors are available for clinical use.

However, topically effective carbonic anhydrase inhibitors are reportedin U.S. Pat. Nos. 4,386,098; 4,416,890; and 4,426,388. The compoundsreported therein are 5 (and 6)-hydroxy-2-benzothiazolesulfonamides andacyl esters thereof.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of this invention have structural formula: ##STR3##or a pharmaceutically acceptable salt thereof, wherein A is C₁₋₈alkylene, either straight or branched chain and either unsubstituted orsubstituted with C₁₋₃ alkoxy or hydroxy;

R is hydrogen or C₁₋₆ alkyl, either straight or branched chain; and

R¹ and R² are independently:

(1) hydrogen,

(2) C₁₋₆ alkyl, either unsubstituted or substituted with one or more of

(a) C₃₋₆ cycloalkyl,

(b) C₁₋₃ alkoxy,

(c) C₁₋₃ alkoxy-(C₂₋₄ alkoxy)_(n) --, wherein n is 1-6

(d) hydroxy,

(e) halo, such as chloro, bromo or fluoro,

(f) C₁₋₃ alkyl--S(O)_(n) --, wherein n is 0-2

(g) phenyl, or

(h) --NR³ R⁴ wherein R³ and R⁴ are independently selected from

(i) hydrogen and

(ii) C₁₋₆ alkyl, either unsubstituted or substituted with one or more ofC₁₋₃ alkoxy, hydroxy or phenyl; ##STR4## wherein R⁵ is C₁₋₄ alkyl eitherstraight or branched chain and either unsubstituted or substituted withone or more of C₁₋₃ alkoxy, or hydroxy; or

(4) taken together with the nitrogen atom to which they are attachedform a 5 to 7-membered heterocycle such as piperidine, morpholine,piperazine, N--C₁₋₃ alkylpiperazine, or thiomorpholine,thiomorpholine-S-oxide, or thiomorpholine-S,S-dioxide.

A preferred embodiment of the novel compounds is that wherein A isjoined to the 5-position of the thieno[2,3-b]thiophene ring system.

It is still more preferred that A is --(CH₂)--₁₋₃, especially --CH₂ --.

It is also preferred that R¹ and R² are independently C₁₋₃ alkoxyethylor C₁₋₃ alkoxy--C₂₋₄ alkoxy-ethyl.

The novel processes for preparing the novel compounds of this inventionare illustrated as follows, wherein Ar represents ##STR5## and A'represents C₀₋₇ alkylene either unsubstituted or substituted with C₁₋₃alkoxy or hydroxy; ##STR6## The process comprises treating the aldehyde,l, in the presence of an acid such as HCl gas with the amine H₂ NR¹ orHNR¹ R² at about 15° to 60° C. in a C₁₋₃ lower alkanol solvent such asmethanol or ethanol for about 0.5 to 72 hours. The crystallineprecipitate 2 or 2a is treated with a complex metal hydride such assodium borohydride in the case of 2 or sodium cyanoborohydride in thecase of 2a at about 0° to 20° C. and continuing stirring for about 0.5to 72 hours. Alternatively, the crystalline precipitate (2 or 2a) may beisolated by filtration and resuspended prior to treatment with thehydride.

Compound 3 is converted into a tertiary amine either by acylation to 4and reduction to 5, or by treatment with ketone 6, followed by reductionto give 7. Conversion of 3 to 4 would be carried out in an aproticsolvent such as ether, THF, or the like in the presence of a base suchas triethylamine at about room temperature, and the subsequent reductionto 5 by BH₃ ·S(CH₃)₂ would be carried out at about room temperature in asolvent such as toluene, CH₂ Cl₂ of THF.

Conversion of 3 to 7 would be carried out by treatment of 3 with anequivalent amount of ketone 6 at about room temperature in a solventsuch as a halocarbon (methylene chloride) or an alcohol such asmethanol.

Alternatively, secondary amine 3 can be converted to tertiary amine 8simply by alkylation. Thus, treatment of 3 in ether, THF, DMF orhalocarbon solution with an alkyl halide, RX, (iodide, bromide orchloride) in the presence of an organic (i--C₃ H₂)₂ N(C₂ H₅) orinorganic (NaHCO₃) base would give 8.

Those novel compounds wherein A is branched chain alkylene can beprepared either from the aldehyde as shown in the above reaction schemeswherein A' is a branched chain alkylene, or from the aromatic aldehydeas shown below: ##STR7## In this process 9 is treated with excessorganolithium reagent R⁸ Li in ether or THF at -78° to -30° . This isquenched with H₂ O and the product extracted. This alcohol is oxidizedto ketone 10 with pyridinium chlorochromate (PCC) in CH₂ Cl₂/tetrahydrofuran at room temperature (2-3 hours). The ketone 10 isreductively aminated with amine R¹ R² NH/Bu₄ NBH₃ CN in an alcohol (CH₃OH) at room temperature for 1 hour to 10 days to provide 11. In thismanner the following compounds are made:

    ______________________________________                                         ##STR8##                                                                     R.sup.1       R.sup.2       R.sup.8                                           ______________________________________                                        CH.sub.3      C.sub.2 H.sub.5                                                                             CH.sub.3                                          CH.sub.2 CH.sub.2 OCH.sub.3                                                                 H             C.sub.2 H.sub.5                                   CH.sub.2 CH.sub.2 F                                                                         CH.sub.3      CH.sub.2 CH.sub.2 OH                              CH.sub.2      CH.sub.2 CH.sub.2 OH                                                                        CH(CH.sub.3).sub.2                                CH.sub.2 CH.sub.2 OH                                                                        CH.sub.2 CH.sub.2 OCH                                                                       CH.sub.2 CH.sub.2 OCH.sub.3                       ______________________________________                                    

The novel pharmaceutical formulations of this invention are adapted fortopical ocular administration in the form of solutions, ointments, solidwater soluble polymeric inserts, or solutions which get at bodytemperature or in the presence of lachrymal fluids for the treatment ofglaucoma and other stages of elevated intraocular pressure and containabout 0.1% to 15% by weight of medicament, especially about 0.5% to 2%by weight of medicament, the remainder being comprised of carriers andother excipients well known in the art.

The medicament in the novel topical ocular formulations comprises one ofthe novel compounds of this invention either alone or in combinationwith a β-adrenergic blocking agent such as timolol maleate or aparasympathomimetic agent such as pilocarpine. In such combinations eachof the active agents is present in an amount approximating that found inits single entity formulations.

The novel method of treatment of this invention comprises the treatmentof elevated intraocular pressure by the administration of an effectiveamount of a novel compound of this invention or a pharmaceuticalformulation thereof. Of primary concern is the treatment by topicalocular administration of about 0.1 to 25 mg and especially 0.2 to 10 mgof such compound per day, either by single dose or on a 2 to 4 dose perday regimen.

EXAMPLE 1 5-Isobutylaminomethylthieno[2,3-b]thiophene-2-sulfonamidehydrochloride Step A: Preparation of Methyl[3-(2-dioxolanyl)-thiophene-2-ylthio]acetate

Thiophene-2-carboxaldehyde ethylene acetal (15.62 g, 0.1 mol) wasdissolved in dry THF (200 ml) in an inert atmosphere and cooled to -74°C. n-Butyl lithium (44 mL of a 2.3M solution in hexane; 0.1 mol) wasadded at a rapid drip rate over 20 minutes (the temperature rose to -68°C.). After the addition was complete, the mixture was stirred at -60° C.to -74° C. for 35 minutes. After about 5 minutes, the lithium derivativebegan to crystallize. Most crystallized after 35 minutes. Sulfur (as afine powder; 3.21 g, 0.1 mol) in 1 g and 2.21 g portions was added 5minutes apart (temperature rose from -74° to -65° C.). The reaction wasstirred at -74° C. for 15 minutes and slowly warmed with stirring to-50° C. where it was held for 15 minutes then warmed to -38° C. over 15minutes. Methyl bromoacetate (9.9 mL, 16.1 g, 0.105 mol) was added at aslow drip rate over a period of 8 minutes (temperature rose from -40° C.to -25° C.) and the reaction mixture was allowed to stir at ambienttemperature until the temperature rose to 0° C. After warming to 24° C.the reaction mixture was stirred at room temperature for 2 hours. Thereaction was worked up by evaporating the solvent in vacuo andpartitioning the residue between ether (250 mL) and water (100 mL). Theether was extracted with water (3×25 mL), dried (MgSO₄), filtered, andthe solvent evaporated in vacuo to leave 23.36 g of crude methyl[3-(2-dioxolanyl)-thiophene-2-ylthio]acetate which was used in the nextstep without purification.

Theoretical Mass, for C₁₀ H₁₂ O₄ S_(2:260).0177150 ; Found: 260.0177150;¹ H NMR(CDCl₃) ω, 3.56(2H, s); 3.71 (3H, s); 4.04 (2H, m); 4.15 (2H, m);6.08 (1H, s); 7.16 (1H, d, J=6 Hz); 7.37 (1H, d, J=6 Hz).

Step B: Preparation of Methyl (3-Formylthiophene-2-ylthio)acetate

To a solution of methyl [3-(2-dioxolanyl)-thiophene-2-ylthio]acetate(23.36 g) in acetone (100 mL) was added p-toluenesulfonic acid (0.25 g)and the reaction mixture was stirred at room temperature for 1 hour. Asaturated aqueous solution of sodium bicarbonate (4 mL) was added withstirring followed by the addition of water (50 mL). After stirring for10 minutes, the acetone was evaporated in vacuo to leave a gum andwater. The gum was dissolved in ether (500 mL) and extracted with water(4×50 mL), dried (MgSO₄), filtered and the solvent was evaporated invacuo to leave 19.77 g of oily methyl(3-formylthiophene-2-ylthio)acetate which was used in the next stepwithout purification.

Step C: Preparation of Methyl thieno[2,3-b]thiophene-2-carboxylate

To a solution of methyl (3-formylthiophene-2-ylthio)acetate (19.31 g, 91mmol) in methanol (150 mL) was added 1,5-diazabicyclo[4.3.0]non-5-ene(DBN) (1 mL, 1 g, 8.05 mmol) and the stirred reaction flask wasimmediately immersed in an ice-water bath. Stirring was continued for 30minutes and the mixture was filtered to give a tacky solid product whichwas washed with a little cold (-20° C.) methanol. The solvent wasevaporated in vacuo from the mother liquor and the residue waspartitioned between ether and aqueous sodium bicarbonate. The waterlayer was washed with ether twice, and the combined ether extracts weredried (MgSO₄), filtered, and the solvent evaporated in vacuo to give anoil which solidified when triturated with a little cold (-20° C.)methanol. This was combined with the original solid product to give atotal of 14.55 g of methyl thieno-[2,3-b]thiophene-2-carboxylate, m.p.101°-105° C. Recrystallization from methanol gave product with m.p.106°-107° C.

Anal. Calc'd for C₈ H₆ O₂ S₂ : C, 48.47; H, 3.05. Found: C, 48.80; H,3.32.

Step D: Preparation of 2-Hydroxymethylthieno[2,3-b]-thiophene

A solution of methyl thieno[2,3-b]thiophene-2-carboxylate (19.8 g, 0.1mol) in dry ether (750 mL) was added at a rapid drip rate (1 hour, 45minutes) to a suspension of lithium aluminum hydride (7.59 g, 0.2 mol)in ether (500 mL) cooled in an ice-water bath. During the addition,precipitated material on the inside of the flask was kept suspended inthe reaction medium. After the addition was complete stirring wascontinued at room temperature for 3 hours. The reaction mixture wascooled in an ice-water bath and there was added in succession, slowly,dropwise with vigorous stirring: water (7.6 ml); 20% aqueous NaOH (22.8mL); water (7.6 mL); water (4 mL); 20% sodium hydroxide (12 mL); water(4 ml). Vigorous stirring was continued until a granular precipitate wasobtained. The ether was decanted and the solids were washed bydecantation three times with ether. The combined ether fractions weredried (MgSO₄), filtered, and evaporated in vacuo to leave 16.33 g ofwhite, solid 2-hydroxymethylthieno[2,3-b]-thiophene, m.p. 85°-87° C.Recrystallization from hexane gave material with m.p. 86°-87° C.

Anal. Calc'd for C₇ H₆ OS₂ : C, 49.38; H, 3.55 Found: C, 49.69; H, 3.72.

Step E. Preparation of Thieno[2,3-b]thiophene-2-carboxaldehyde

2-Hydroxymethylthieno[2,3-b]thiophene (16.33 g, 95.9 mmol) dissolved inmethylene chloride (165 mL) is added all at once to a stirred suspensionof pyridinium chlorochromate (31.0 g, 143.9 mmols) in methylene chloride(172 mL) and stirring was continued at ambient temperature for 2 hours.The mixture was diluted with ether (288 mL) and the supernatant wasdecanted. The solids were washed three times by trituration with ether.The combined ether extracts were filtered through a 60×150 mm silica gel(230-400 mesh) column under pressure and followed with 3 portions ofether. The ether phase of the combined filtrates was evaporated in vacuoto give 13.86 g, of thieno[2,3-b]thiophene-2-carboxaldehyde, m.p.43°-45° C. Sublimation at 108° C. bath temperature and 0.5 mm pressuregave 13.10 g, m.p. 47°-48° C.

Anal. Calc'd for C₇ H₄ OS₂ : C, 49.98; H, 2.40. Found: C, 50.25; H,2.45.

Step F: Preparation of 2-(2-dioxolanyl)thieno[2,3-b]thiophene

p-Toluenesulfonic acid (150 mg) is added to a stirred two phase mixtureof thieno[2,3-b]thiophene-2-carboxaldehyde (8.06 g, 47.91 mmol);ethylene glycol (21.4 g, 345 mmols); methyl orthoformate (30.51 g, 287.5mmols); and toluene (50 mL). The reaction quickly became homogeneous andstirring was continued with the reaction immersed in an oil bath at 45°to 50° C. A gentle vacuum was applied through an air condenser every 30to 60 minutes for 5 hours and the reaction was stirred at 45°-50° C.overnight. The reaction was cooled in an ice-water bath and pyridine(0.5 mL) was added. The solvent and volatiles were evaporated in vacuo.The remaining oil was dissolved in ether (250 mL) and extracted with asaturated solution of sodium bicarbonate (2×50 mL), then water (4×50mL), dried (MgSO₄), filtered, and the volumn of ether reduced to about75 mL in vacuo as the product began to crystallize. The crystals werecollected and washed with a little 40% ether in hexane giving 4.08 g ofwhite, solid 2-(2-dioxolanyl)-thieno-[2,3-b]thiophene, m.p. 92°-93° C.The ether from the mother liquors was further reduced in volumn and thenallowed to crystallize, to give another 0.76 g of pure product, m.p.96°-97° C. Both fractions were homogeneous by tlc, and were combined(4.84g) for use in the next step.

Anal. Calc'd for C₉ H₈ O₂ S₂ : C, 50.92; H, 3.80.Found: C, 51.26; H,3.93.

Note: This reaction proceeds through the intermediatethieno[2,3-b]thiophene-2-carboxaldehyde dimethyl acetal which was notisolated.

Step G: Preparation of5-(2-Dioxolanyl)thieno[2,3-b]thiophene-2-sulfonamide

To a cooled mixture of 2-(2-dioxolanyl)-thieno[2,3-b]thiophene (2.12 g,10 mmol) in dry THF (20 mL) in a nitrogen atmosphere was added butyllithium (4.4 mL of a 2.3M solution in hexane; 10 mmols) dropwise bysyringe over a period of 30 minutes with magnetic stirring. Stirring wascontinued at -75° C. for 30 minutes. A rapid stream of dry gaseous SO₂was directed at the surface of the stirred mixture at -75° C. Theinternal reaction temperature rose to -40° C. then cooled to -75° C.again. The SO₂ stream was continued for 30 minutes then the reaction wasallowed to warm to 10° C. while stirring using the SO₂ stream. Theexcess SO₂ and solvent were then evaporated in vacuo to leave 7.09 g oflithium sulfonic acid salt. The salt was dissolved in a saturatedsolution of sodium bicarbonate (15 mL) and cooled in an ice-water bath.N-chlorosuccinimide (2.00 g, 15 mmol) was added in small portions over a15 minute period. The reaction was stirred in an ice-water bath for 1hour, and was then extracted with chloroform three times. The combinedextracts were dried (MgSO₄), filtered, and the solvent was removed invacuo to leave 2.73 g of sulfonyl chloride. This intermediate wasdissolved in acetone (5 mL) and added dropwise over 30 minutes to an icecold concentrated ammonium hydroxide solution (15 mL), which was thenstirred at ice bath temperature for 1.5 hours. The acetone and ammoniawere removed in vacuo leaving a suspension of crystalline product inwater. The crystals were collected, washed with water, and dried in avacuum oven at room temperature with a slow stream of air through theoven to give 1.76 g of crude crystalline5-(2-dioxolanyl)thieno[2,3-b]thiophene-2-sulfonamide. Recrystallizationfrom nitromethane (Aldrich-Gold label) gave 1.43 g product, whichpartially melted at 220° C., resolidified and melted >320° C.

¹ H NMR, (DMSO-d₆), ω 3.98; (2H, m); 4.06 (2H, m); 6.09 (1H, s); 7.50(1H, s); 7.73 (2H, s).

Anal. Calc'd for C₉ H₉ NO₄ S₃ : 37.10; H, 3.11; N, 4.81. Found: 37.42;H, 3.05; N, 4.92.

Step H: Preparation of 5-Formylthieno[2,3-b]thiophene-2-sulfonamide

5-(2-Dioxolanyl)thieno[2,3-b]thiophene-2-sulfonamide (2.59 g, 8.89 mmol)was suspended in acetone and p-toluenesulfonic acid (2.50 g, 13.1 mmol)was added. The mixture was stirred at room temperature for one hour atwhich time a solution was obtained. Water (2.0 mL) was added andstirring continued for 3 hours. A saturated solution of sodiumbicarbonate (30 mL) was added dropwise, followed by the slow addition ofwater (40 mL). The resulting solution or mixture was seeded with a fewcrystals of product and the acetone was evaporated in vacuo. Thecrystals were collected, washed with water and dried in vacuo to give2.10 g of 5-formylthieno[2,3-b]thiophene-2-sulfonamide, m.p. 188°-189°C. This product was used in the next step without further purification.

Anal. Calc'd for C₇ H₅ NO₃ S₃ : C, 34.00; H, 2.04; N, 5.66. Found: C,34.18; H, 1.99; N, 5.58.

Step I: Preparation of5-Isobutyliminomethylthieno-[2,3-b]thiophene-2-sulfonamide

5-Formylthieno[2,3-b]thiophene-2-sulfonamide (1.48 g, 6 mmol) wassuspended in methanol (15 mL) and isobutylamine (4.2 mL, 3.07 g, 42mmols) was added all at once. After a solution was obtained, methanolicHCl (1.8 mL of a 6.70 molar solution of HCl in methanol) was addedrapidly. The resulting mixture was stoppered and heated to near refluxfor 2 to 5 minutes and then allowed to stand at room temperature untilthe product crystallized. After cooling, the crystals were collected andwashed with a little cold (-20° C.) methanol. The crystals were dried invacuo to give 1.31 g of5-N-isobutyliminomethylthieno[2,3-b]thiophene-2-sulfonamide, m.p.204°-206° C. (dec).

Step J: Preparation of5-Isobutylaminomethylthieno-[2,3-b]thiophene-2-sulfonamide

5-N-Isobutyliminomethylthieno[2,3-b]thiophene-2-sulfonamide (1.30 g,4.30 mmols) was dissolved in methanol (15 mL) and THF (15 mL) and thesolution was cooled in an ice-water bath. To this cooled solution wasadded sodium borohydride 95 mg (2.5 mmol) three times at 30 minuteintervals with 30 minutes of stirring after the last addition. Water wasadded and the mixture was stirred at room temperature for 1 hour. Themethanol and THF were evaporated in vacuo and the resulting crystallinemass was collected and washed twice with water by trituration. Theproduct was dried in vacuo at room temperature to give 1.20 g of5-isobutylaminomethylthieno[2,3-b]thiophene-2-sulfonamide which was usedin the next step without further purification.

Step K: Preparation of5-Isobutylaminomethylthieno-[2,3-b]thiophene-2-sulfonamide hydrochloride

5-Isobutylaminomethylthieno[2,3-b]thiophene-2-sulfonamide (0.95 g, 3.12mols) is dissolved in 58 mL of absolute ethanol and filtered. EthanolicHCl (0.80 mL of a 5.10 M solution of HCl in ethanol; 4.08 mmols) wasadded and the reaction swirled and then allowed to stand. The resultingcrystals are collected, washed with absolute ethanol twice, then washedwith ether twice and dried in vacuo to give 0.98 g of5-isobutylaminomethylthieno[2,3-b]thiophene-2-sulfonamide hydrochloride,m.p. 251°-252° C.

Anal. Calc'd for C₁₁ H₁₇ ClN₂ O₂ S₃ : C, 38.75; H, 8.22; N, 5.03. Found:C, 39.01; H, 8.28; N, 5.07.

EXAMPLE 2 Step A: Preparation of5-t-Butylaminomethylthieno-[2,3-b]thiophene-2-sulfonamide

t-Butylamine (0.736 mL, 0.512 g, 7 mmol) was added to a suspension of5-formylthieno[2,3-b]-thiophene (0.247 g, 1 mmol) in methanol (2.5 mL).The mixture was warmed gently to obtain solution. Methanolic HCl (0.30mL of a 6.70 M solution of HCl in methanol; 2 mmol) was added and themixture was warmed with stirring to 50° C. and stirred at roomtemperature for 1 hour. THF (2.5 mL) was added to effect solution andthe mixture was cooled in an ice-water bath. Sodium borohydride (0.183g, 4.84 mmols) was added all at once with stirring and stirring wascontinued for 30 minutes with tlc (10% methanol in chloroform saturatedwith ammonia and water-silica gel) showed the reaction to be complete.The product was worked up by adding water (50 mL) and 1N HCl to pH 9.The crystalline product was collected and washed with water and dried invacuo to give 0.25 g of5-t-butylaminomethylthieno[2,3-b]-thiophene-2-sulfonamide, m.p.208°-209° C. (dec).

Step B: Preparation of5-t-Butylaminomethylthieno-[2,3-b]thiophene-2-sulfonamide hydrochloride

Substituting 5-t-butylaminomethylthieno-[2,3-b]thiophene-2-sulfonamidefor the isobutyl compound in Example 1, Step K, gave the title compound,m.p. 292°-293° C. (dec); (placed in bath at 285° C.).

Anal. Calc'd for C₁₁ H₁₇ ClN₂ O₂ S₃ : C, 38.75; H, 5.03; N, 8.22. Found:C, 39.12; H, 5.28; N, 8.40.

EXAMPLE 3 5-Methylaminomethylthieno[2,3-b]thiophene-2-sulfonamidehydrochloride

Substituting methylamine (as a titrated methylamine solution inmethanol) for isobutylamine in Example 1, Step I, and then proceedingsubstantially as described in Steps J and K gave the title compoundafter recrystallization from methanol, m.p. 263°-264° C.(dec).

Anal. Calc'd for C₈ H₁₁ ClN₂ O₂ S₃ : C, 32.15; H, 3.37; N, 9.37. Found:C, 32.30; H, 3.49; N, 9.27.

EXAMPLE 45-(4-Hydroxybutylaminomethyl)thieno[2,3-b]thiophene-2-sulfonamidehydrochloride

Employing the procedures substantially as described in Example 1, StepI, but replacing the isobutylamine with 4-hydroxybutylamine andproceeding as described through Steps J and K gave the title compound,m.p. 200°-202° C. (dec).

Anal. Calc'd for C₁₁ H₁₇ ClN₂ O₃ S₃ : C, 37.02; H, 4.80; N, 7.85. Found:C, 36.99; H, 4.89; N, 7.87.

EXAMPLE 55-(2-Hydroxyethylaminomethyl)thieno[2,3-b]thiophene-2-sulfonamidehydrochloride

Substituting 2-hydroxyethylamine for t-butylamine in Step A of Example 2and proceeding through Step B gave the title compound, m.p. 209°-210° C.

Anal. Calc'd for C₉ H₁₃ ClN₂ O₃ S₃ : C, 32.87; H, 3.98; N, 8.52. Found:C, 32.70; H, 4.11; N, 8.89.

EXAMPLE 65-(1,2-Dihydroxy-3-propylaminomethyl)thieno[2,3-b]-thiophene-2-sulfonamidehydrochloride

1,2-Dihydroxy-3-propylamine was substituted for isobutylamine in Step Iof Example 1 followed by Steps J and K with the following modificationin Step J: upon addition of water and evaporating the organic solvent invacuo a small amount of precipitate was obtained which was filtered off.The pH of the clear resulting solution was adjusted to 8.5 with dilutedaqueous sodium hydroxide solution and nearly all of the water wasevaporated in vacuo. The resulting gum was extracted by shaking anddecanting with ethyl acetate ten times or until no more U.V. positivematerial was extracted. The combined ethyl acetate extracts were dried(MgSO₄), filtered and the solvent evaporated leaving the desired amine.The hydrochloride salt was made in accordance with Example 1, Step K togive the title compound, m.p. 184°-186° C. (dec).

Anal. Calc'd for C₁₀ H₁₅ ClN₂ O₄ S₃.0.15 mole EtOH: C, 34.47; H, 4.38;N, 7.66.Found: C, 34.30; H, 4.33; N, 7.97.

EXAMPLE 75-(Cyclopropylmethylaminomethyl)thieno[2,3-b]-thiophene-2-sulfonamidehydrochloride

Substituting cyclopropylmethylamine for isobutylamine in Step I ofExample 1 and proceeding through Step K (but with the addition ofexactly one equivalent of HCl as ethanolic HCl in Step K) gave the titlecompound, m.p. 264°-265° C. (dec).

Anal. Calc'd for C₁₁ H₁₅ ClN₂ O₂ S₃ : C, 38.99; H, 4.46; N, 8.27. Found:C, 39.04; H, 4.52; N, 8.29.

EXAMPLE 85-[(N-Methoxyethyl-N-methoxyethoxyethyl)aminomethyl]-thieno[2,3-b]thiophene-2-sulfonamideStep A: Preparation of5-[(N-Methoxyethyl-N-methoxyethoxyethyl)aminomethyl]thieno[2,3-b]thiophene-2-sulfonamide

N-Methoxyethyl-N-methoxyethoxyethylamine (36.0 g., 203 mmoles) wasdissolved in methanol (112 mL). To this solution was added methanolicHCl(5.554M in MeOH) (28.2 mL), 157 mmoles) and this was stirred for 10minutes. 5-Formylthieno[2,3-b]-thiophene-2-sulfonamide(8.80 g., 35.6mmoles) was added and the mixture was stirred for 24 hours. 4°A sieves(23.7 g.) were added and the mixture under Argon was stirred for anadditional 6 days. Sodium cyanoborohydride (4.47 g. 71.2 mmoles) wasadded and this was stirred under Argon for 48 hours. Methanol (250 mL)and THF (250 mL.) were added to dissolve all the product. The solutionwas then filtered through a pad of celite and all solvent was evaporatedin vacuo. H₂ O (100 mL) was added followed by the slow addition of conc.HCl (100 mL). The liquid was decanted and filtered from solid. The acidsolution of product was saved. More product was recovered from insolublematerial by dissolving the insoluble material in THF (100 mL). Conc. HCl(25 mL) was added and the solution heated to reflux three times in a 15minute interval. 100 ml of water was added and the THF evaporated off. Aclear solution was decanted from the insoluble material. To the combinedacidic water solution of product was added conc. NH₄ OH until pH was 8.5(125 mL), and this was then extracted five times over MgSO₄. The solventwas filtered and evaporated in vacuo to leave 10.16 g of crude product,which was chromatographed on 2.4 kg. of silica gel, eluting with 3%methanol in chloroform to give 7.7 g of highly pure5-[(N-methoxyethyl-N-methoxyethoxyethyl)-aminomethyl]thieno[2,3-b]thiophene-2-sulfonamide.

Step B: Preparation of5-[(N-Methoxyethyl-N-methoxyethoxyethyl)aminomethyl]thieno[2,3-b]thiophene-2-sulfonamidehydrochloride

5-[(N-Methoxyethyl-N-methoxyethoxyethyl)aminomethyl]-thieno[2,3-b]thiophene-2-sulfonamide(6.42 g., 15.71 mmole) from Step A was dissolved in i-propanol (550 mL)filtered and methanolic HCl (5.54M) (3.00 mL; 16.6 mmole) was added. Theresulting mixture was swirled, allowed to stand for 15 minutes, and wasboiled down to 200 mL and seeded. On cooling most of the product oiledout. A crust of crystals formed and this was broken up by trituration toprovide 5.64 g of pure5-[(N-Methoxyethyl-N-methoxyethoxyethyl)aminomethyl]-thieno[2,3-b]thiophene-2-sulfonamidehydrochloride, mp 147°-148° C.

Anal. Calc'd for C₁₅ H₂₅ ClN₂ O₅ S₃ : C, 40.48; H, 5.66; N, 6.30 Found:C, 40.52; H, 5.28; N, 6.30.

EXAMPLE 95-(2-Methoxyethylaminomethyl)thieno[2,3-b]thiophene-2-sulfonamidehydrochloride

Substituting 2-methoxyethylamine for isobutylamine in Step I of Example1 and proceeding through Step K gave the title compound, m.p. 223°-224°C.

Anal. Calc'd for C₁₀ H₁₅ ClN₂ O₃ S₃ : C, 35.03; H, 4.41; N, 8.17 Found:C, 35.04; H, 4.46; N, 8.03

Employing the procedures described in the foregoing the compoundsdepicted in the following table are prepared from the appropriatestarting materials.

                                      TABLE                                       __________________________________________________________________________     ##STR9##                                                                                                     melting or                                    A      R.sup.1 R.sup.2     R    decomposition point (°C.)              __________________________________________________________________________    5-CH.sub.2                                                                           H       CH.sub.3 O(CH.sub.2).sub.3                                                                H    230-232 (HCl)                                 5-CH.sub.2                                                                           H       CH.sub.3 O(CH.sub.2).sub.2 O(CH.sub.2).sub.3                                              H    (154-155) +                                                                   244-245 (HCl)                                 5-CH.sub.2                                                                           CH.sub.2 CH.sub.2OCH.sub.2 CH.sub.2*                                                              H    264-265 (HCl)                                 5-CH.sub.2                                                                           H       CF.sub.3 CH.sub.2                                                                         H    230-232 (HCl)                                 5-CH.sub.2                                                                           H       CH.sub.3 S(CH.sub.2).sub.2                                                                H    224-225 (HCl)                                 5-CH.sub.2                                                                           H       f(CH.sub.2).sub.2                                                                         H    221-222 (HCl)                                 5-CH.sub.2                                                                           CH.sub.3 O(CH.sub.2).sub.2                                                            CH.sub.3 O(CH.sub.2).sub.2*                                                               H    (155-157) +                                                                   190-192 (HCl)                                 5-CH.sub.2                                                                           H                                                                                      ##STR10##  H    110-112 (HCl)                                 5-CH.sub.2                                                                           CH.sub.2 CH.sub.2 SCH.sub.2 CH.sub.2                                                              H    248 250 (HCl)                                 5-CH.sub.2                                                                           CH.sub.3                                                                              CH.sub.3    H                                                  4-CH.sub.2                                                                           CH.sub.3                                                                              CH.sub.3    H                                                  5-CH.sub.2                                                                           C.sub.2 H.sub.5                                                                       C.sub.6 H.sub.5 CH.sub.2                                                                  H                                                  5-CH.sub.2                                                                           H       C.sub.2 H.sub.5                                                                           4-CH.sub.3                                         5-CH.sub.2 CH.sub.2                                                                  CH.sub.3                                                                              CH.sub.3    H                                                  5-CH.sub.2 CH.sub.2                                                                  i-C.sub.4 H.sub.9                                                                     H           4-CH.sub.3                                         4-CH.sub.2                                                                           CH.sub.3                                                                              CH.sub.3 OCH.sub.2 CH.sub.2                                                               H                                                  5-CH.sub.2                                                                           H       (CH.sub.3).sub.2 NCH.sub.2                                                                H                                                  __________________________________________________________________________     *Intermediate iminium compound was reduced with sodium cyanoborohydride.      + Compound scinters or melts at parenthetical temperature, resolidifies       and melts or decomposes at higher temperature.                           

EXAMPLE 10

    ______________________________________                                        EXAMPLE 10                                                                    ______________________________________                                        5 isobutylaminomethylthieno-                                                                      1      mg      15   mg                                    [2,3-b]thiophene-2-sulfon-                                                    amide hydrochloride                                                           Monobasic sodium phosphate 2H.sub.2 O                                                             9.38   mg      6.10 mg                                    Dibasic sodium phosphate .12H.sub.2 O                                                             28.48  mg      16.80                                                                              mg                                    Benzalkonium chloride                                                                             0.10   mg      0.10 mg                                    Water for injection q.s. ad.                                                                      1.0    ml      1.0  ml                                    ______________________________________                                    

The novel compound, phosphate buffer salts, and benzalkonium chlorideare added to and dissolved in water. The pH of the composition isadjusted to 5.4-7.4 and diluted to volume. The composition is renderedsterile by ionizing radiation.

EXAMPLE 11

    ______________________________________                                        EXAMPLE 11                                                                    ______________________________________                                        5-t-Butylaminomethylthieno-                                                                           5 mg                                                  [2,3-b]thiophene-2-                                                           sulfonamide                                                                   petrolatum q.s. ad.     1 gram                                                ______________________________________                                    

The compound and the petroleum are aseptically combined.

EXAMPLE 12

    ______________________________________                                        EXAMPLE 12                                                                    ______________________________________                                        5-Methylaminomethylthieno-                                                                             1 mg                                                 [2,3-b]thiophene-2-sulfon-                                                    amide hydrochloride                                                           Hydroxypropylcellulose q.s.                                                                           12 mg                                                 ______________________________________                                    

Ophthalmic inserts are manufactured from compression molded films whichare prepared on a Carver Press by subjecting the powdered mixture of theabove ingredients to a compressional force of 12,000 lbs. (gauge) at300° F. for one to four minutes. The film is cooled under pressure byhaving cold water circulate in the platen. Ophthalmic inserts are thenindividually cut from the film with a rod-shaped punch. Each insert isplaced into a vial, which is then placed in a humidity cabinet (88% R.H.at 30° C.) for two to four days. After removal from the humiditycabinet, the vials are stoppered and then capped. The vials containingthe hydrate insert are then autoclaved at 250° F. for 1/2 hour.

What is claimed is: 1.5-[N-Methoxyethyl-N-methoxyethoxyethyl)amino-methyl]thieno[2,3-b]thiophene-2-sulfonamide.2. An ophthalmological formulation for the treatment of ocularhypertension and glaucoma comprising an ophthalmologically acceptablecarrier and an effective ocular antihypertensive amount of the compoundof claim
 1. 3. A method of treating ocular hypertension and glaucomawhich comprises the topical ocular administration to a patient in needof such treatment of an effective ocular antihypertensive amount of thecompound of claim 1.